Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF TREATMENT AND/OR PREVENTION OF MAJOR ADVERSE CARDIOVASCULAR
EVENTS (MACE) WITH A COMBINATION OF A BET BROMODOMAIN INHIBITOR AND A
SODIUM DEPENDENT GLUCOSE TRANSPORT 2 INHIBITOR
[0001] This application claims the benefit of priority of U.S. Provisional
Application No.
62/930,860, filed November 5, 2019, the entire disclosure of which is
incorporated herein by
reference.
[0002] The present disclosure relates to methods of treating and/or preventing
Major
adverse cardiovascular events (MACE) (including non-fatal myocardial
infarction, cardiovascular
death, stroke, and hospitalization for cardiovascular disease (CVD) events) by
administering to a
subject in need thereof, a combination of a sodium-glucose transport protein 2
(SGLT2)
inhibitor and a compound of Formula I or a stereoisomer, tautomer,
pharmaceutically
acceptable salt, or hydrate thereof.
[0003] Compounds of Formula I have previously been described in U.S. Patent
8,053,440, incorporated herein by reference. Compounds of Formula I include:
R5
H R6
(R4)P
1
I.
R3 N
W R7
1
N H
R2 H
R1
0
Formula I
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate
thereof,
wherein:
R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen,
and
hydrogen;
R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen,
and hydrogen;
R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen,
and
hydrogen;
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R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and
alkoxy;
W is selected from C and N, wherein if W is N, then p is 0 or 1, and if W is
C, then p is 1;
and
for W-(R4), W is C, p is 1 and R4 is H, or W is N and p is 0.
[0004] Despite the use of modern evidence-based therapies including prompt
coronary
revascularization, dual anti-platelet therapy, and intensive lipid lowering
therapy, major
adverse cardiovascular events (MACE) recur with high frequency after an acute
coronary
syndrome (ACS). Patients with type 2 diabetes (T2DM) has a particular high
risk and represents
about one third of ACS cases (Cannon et al. 2015; Schwartz et al. 2013;
Schwartz et al. 2018).
[0005] New therapies, such as SGLT2 inhibitors, which induce the secretion of
glucose
in the urine by inhibition of sodium glucose transport protein 2 (Zinman et
al. 2015; Neal et al.
2017; Perkovic et al. 2019) has shown reduction of cardiovascular-related
disorder risk in
patients with established cardiovascular disease, diabetes and chronic kidney
disease (Zinman
et al. 2015; Neal et al. 2017; Perkovic et al. 2019). However, no diabetes
medication has been
shown to reduce MACE in patients with recent ACS and substantial residual risk
remains for this
population.
[0006] The ability of SGLT2 inhibitors in reducing MACE in type 2 diabetes
patients has
been studied in several clinical trials, such as EMPA-REG OUTCOME for
empaglifozin
(NCT01131676); CANVAS Program for canaglifozin (NCT01032629 and NCT01989754);
and
DECLARE-TIMI (NCT01730534) for dapaglifozin. To summarize, empaglifozin was
shown to have
the ability to mildly reduce narrowly defined MACE by 14% (Hazard Ratio [HR],
0.86; 95%Cl,
0.74-0.99) and broadly defined MACE by 11% (HR 0.89, 95%Cl, 0.78-1.01)
(Guettier, J.M.
Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Meeting, June
28, 2016, U.S.
Food and Drug Administration (FDA)). However, with the exception of
cardiovascular deaths
(HR 0.62, 95% Cl, 0.49-0.77), empaglifozin did not show any reduction in the
individual MACE
events (i.e., HR 1.0) (Rastogi et al. (2017) Diabetes Ther, 8:1245-1251).
Canaglifozin was also
shown to have the ability to mildly reduce narrowly defined MACE by 14% (HR
0.86, 95% Cl,
0.75-0.97) (Carbone et al. (2019) Cardiovasc Diabetol, 18(64):1-13). Although
canaglifozin was
associated with reductions in the individual MACE events, these individual
effects did not reach
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statistical significance (Carbone etal.). As for dapagliflozin, treatment with
this SGLT2 did not
result in a higher or lower rate of narrowly defined MACE than placebo (HR
0.93, 95% Cl, 0.82-
1.04) but did result in a modest reduction of 17% in cardiovascular death or
hospitalization for
heart failure (HR 0.83, 95% Cl, 0.73-0.95) (Wiviott etal., N Engl J Med,
380(4):347-357). A
recently completed clinical Phase 3 trial (BETonMACE; NCT02586155) evaluated
the effect on
MACE of apabetalone (RVX-208) in type 2 diabetes patients with low HDL
cholesterol (below
40mg/dL for males and below 45 mg/dL for females) and a recent ACS (preceding
7-90 days).
All patients received high intensity statin treatment as well as other
evidence-based
treatments. The study enrolled 2,425 patients and the MACE outcome population
consisted of
2,418 patients. A total of 150 patients received both RVX-208 and an SGLT2
inhibitor; a total of
148 received an SGLT2 inhibitor, but no RVX-208; a total of 1,062 received RVX-
208, but no
SGLT2 inhibitor; a total of 1,058 received neither RVX-208 or an SGLT2
inhibitor.
[0007] Surprisingly, as detailed in Example 2, we found that patients treated
with the
combination RVX-208 and an SGLT2 inhibitor showed pronounced reduction of
cardiovascular-
related disorders and cardiovascular disease (CVD) events, as measured by MACE
reduction,
compared to treatment with either therapy alone. The results discussed in
Example 2
consistently demonstrate that apabetalone by itself has the ability to reduce
hazard ratios or
the number of patients having a MACE event (as a single composite end point of
the events
non-fatal myocardial infarction, cardiovascular death, stroke and optionally
hospitalization for
cardiovascular diseases) or a specific MACE event such as myocardial
infarction, cardiovascular
death, hospitalization for cardiovascular diseases and hospitalization for
congestive heart
failure (see Figures 2, 5, 8, 11, 14, and 17). However, when apabetalone was
combined with a
SGLT2 inhibitor, the number of patients having a MACE event as a whole or a
specific individual
MACE event as described above was unexpectedly and consistently reduced to an
extent that
reached statistical significance and far exceeded the additive effects of
apabetalone and the
SGLT2 inhibitor individually (e.g., at least about 50% and up to about 70%;
see Figures 1, 3, 4, 6,
7, 9, 10, 12, 13, 15, 16, and 18) and SGLT2 monotherapy clinical trial results
described above.
[0008] The effect of the co-administration of RVX-208 and SGLT2 inhibitors ¨
quantified
using cardiovascular-related disorders adjudicated by an independent medical
advisory
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committee -- illustrated a significant reduction of events compared to placebo
and SGLT2
inhibitors [HR = 0.40 (95% Cl, 0.16 ¨ 1.00; p=0.05)].
[0009] The present invention provides methods of treating and/or preventing
Major
adverse cardiovascular events (MACE) (including non-fatal myocardial
infarction, cardiovascular
death, stroke, and hospitalization for CVD events) by administering to a
subject in need thereof,
a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of
Formula I or a
stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
[0010] In some embodiments, the invention provides methods of preventing
cardiovascular death by administering to a subject in need thereof, a sodium-
glucose transport
protein 2 (SGLT2) inhibitor and a compound of Formula I or a stereoisomer,
tautomer,
pharmaceutically acceptable salt, or hydrate thereof.
[0011] In some embodiments, the invention provides methods of treating and/or
preventing hospitalization for CVD events by administering to a subject in
need thereof, a
sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula
I or a
stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
[0012] In some embodiments, the invention provides methods of treating and/or
preventing a non-fatal myocardial infarction by administering to a subject in
need thereof, a
sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula
I or a
stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
[0013] In some embodiments, the compound of Formula I is administered
simultaneously with a SGLT2 inhibitor. In some embodiments, the Compound of
Formula I is
administered sequentially with the SGLT2 inhibitor. In some embodiments, the
Compound of
Formula I is administered in a single pharmaceutical composition with the
SGLT2 inhibitor. In
some embodiments, the Compound of Formula I and the SGLT2 inhibitor are
administered as
separate compositions.
[0014] In some embodiments, the compound of Formula la is selected from
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R5
H R6
(R4)P
I
R3 w1 .
N N R7
H
R2 H
R1
0
Formula la
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate
thereof,
wherein:
R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen;
R2 is selected from alkoxy, alkyl, and hydrogen;
R5 and R7 are each independently selected from alkyl, alkoxy, and hydrogen;
R6 is selected from alkyl, hydroxyl, and alkoxy;
W is selected from C and N, wherein if W is N, then p is 0 or 1, and if W is
C, then p is 1;
and
for W-(R4), W is C, p is 1 and R4 is H, or W is N and p is 0.
[0015] In some embodiments, the Compound of Formula 1 is 2-(4-(2-
hydroxyethoxy)-
3,5-dimethylpheny1)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222)
or a
pharmaceutically acceptable salt thereof.
[0016] In some embodiments, the SGLT2 inhibitor is empagliflozin,
canagliflozin,
dapagliflozin, remogliflozin, ipragliflozin, or HM41322. In some embodiments,
the SGLT2
inhibitor is bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, or
tofogliflozin.
[0017] In some embodiments, the MACE endpoint is narrowly defined as a single
composite endpoint of cardiovascular (CV) death, non-fatal myocardial
infarction, or stroke.
[0018] In some embodiments, the MACE endpoint is broadly defined as a single
composite endpoint of cardiovascular (CV) death, non-fatal myocardial
infarction,
hospitalization for CVD events, or stroke.
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Brief Description of the Drawings
[0019] Figure 1 depicts a comparison of the cumulative incidence of narrowly
defined
MACE in patients administered RVX-208 with SGLT2 inhibitors versus patients
administered
placebo with SGLT2 inhibitors.
[0020] Figure 2 depicts a comparison of the cumulative incidence of narrowly
defined
MACE in patients administered RVX-208 without SGLT2 inhibitors versus patients
administered
placebo without SGLT2 inhibitors.
[0021] Figure 3 depicts a comparison of the cumulative incidence of narrowly
defined
MACE in patients administered RVX-208 with SGLT2 inhibitors versus patients
administered
RVX-208 without SGLT2 inhibitors.
[0022] Figure 4 depicts a comparison of the cumulative incidence of broadly
defined
MACE in patients administered RVX-208 with SGLT2 inhibitors versus patients
administered
placebo with SGLT2 inhibitors.
[0023] Figure 5 depicts a comparison of the cumulative incidence of broadly
defined
MACE in patients administered RVX-208 without SGLT2 inhibitors versus patients
administered
placebo without SGLT2 inhibitors.
[0024] Figure 6 depicts a comparison of the cumulative incidence of broadly
defined
MACE in patients administered RVX-208 with SGLT2 inhibitors versus patients
administered
RVX-208 without SGLT2 inhibitors.
[0025] Figure 7 depicts a comparison of the cumulative incidence of non-fatal
myocardial infarction in patients administered RVX-208 with SGLT2 inhibitors
versus patients
administered placebo with SGLT2 inhibitors.
[0026] Figure 8 depicts a comparison of the cumulative incidence of non-fatal
myocardial infarction in patients administered RVX-208 without SGLT2
inhibitors versus
patients administered placebo without SGLT2 inhibitors.
[0027] Figure 9 depicts a comparison of the cumulative incidence of non-fatal
myocardial infarction in patients administered RVX-208 with SGLT2 inhibitors
versus patients
administered RVX-208 without SGLT2 inhibitors.
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[0028] Figure 10 depicts a comparison of the cumulative incidence of CV deaths
in
patients administered RVX-208 with SGLT2 inhibitors versus patients
administered placebo with
SGLT2 inhibitors.
[0029] Figure 11 depicts a comparison of the cumulative incidence of CV deaths
in
patients administered RVX-208 without SGLT2 inhibitors versus patients
administered placebo
without SGLT2 inhibitors.
[0030] Figure 12 depicts a comparison of the cumulative incidence of CV deaths
in
patients administered RVX-208 with SGLT2 inhibitors versus RVX-208 without
SGLT2 inhibitors.
[0031] Figure 13 depicts a comparison of the cumulative incidence of
hospitalization for
CVD events in patients administered RVX-208 with SGLT2 inhibitors versus
patients
administered placebo with SGLT2 inhibitors.
[0032] Figure 14 depicts a comparison of the cumulative incidence of
hospitalization for
CVD events in patients administered RVX-208 without SGLT2 inhibitors versus
patients
administered placebo without SGLT2 inhibitors.
[0033] Figure 15 depicts a comparison of the cumulative incidence of
hospitalization for
CVD events in patients administered RVX-208 with SGLT2 inhibitors versus
patients
administered RVX-208 without SGLT2 inhibitors.
[0034] Figure 16 depicts a comparison of the cumulative incidence of
hospitalization for
congestive heart failure in patients administered RVX-208 with SGLT2
inhibitors versus patients
administered placebo with SGLT2 inhibitors.
[0035] Figure 17 depicts a comparison of the cumulative incidence of
hospitalization for
congestive heart failure in patients administered RVX-208 without SGLT2
inhibitors versus
patients administered placebo without SGLT2 inhibitors.
[0036] Figure 18 depicts a comparison of the cumulative incidence of
hospitalization for
congestive heart failure in patients administered RVX-208 with SGLT2
inhibitors versus patients
administered RVX-208 without SGLT2 inhibitors.
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Definitions
[0037] By "optional" or "optionally" is meant that the subsequently described
event or
circumstance may or may not occur, and that the description includes instances
where the
event or circumstance occurs and instances in which is does not. For example,
"optionally
substituted aryl" encompasses both "aryl" and "substituted aryl" as defined
below. It will be
understood by those skilled in the art, with respect to any group containing
one or more
substituents, that such groups are not intended to introduce any substitution
or substitution
patterns that are sterically impractical, synthetically non-feasible and/or
inherently unstable.
[0038] As used herein, the term "hydrate" refers to a crystal form with either
a
stoichiometric or non-stoichiometric amount of water is incorporated into the
crystal structure.
[0039] The term "alkenyl" as used herein refers to an unsaturated straight or
branched
hydrocarbon having at least one carbon-carbon double bond, such as a straight
or branched
group of 2-8 carbon atoms, referred to herein as (C2-C8) alkenyl. Exemplary
alkenyl groups
include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl,
butadienyl, pentadienyl,
hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)-
pentenyl.
[0040] The term "alkoxy" as used herein refers to an alkyl group attached to
an oxygen
(0-alkyl). "Alkoxy" groups also include an alkenyl group attached to an oxygen
("alkenyloxy") or
an alkynyl group attached to an oxygen ("alkynyloxy") groups. Exemplary alkoxy
groups include,
but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-8
carbon atoms,
referred to herein as (C1-C8) alkoxy. Exemplary alkoxy groups include, but are
not limited to,
methoxy and ethoxy.
[0041] The term "alkyl" as used herein refers to a saturated straight or
branched
hydrocarbon, such as a straight or branched group of 1-8 carbon atoms,
referred to herein as
(C1-C8) alkyl. Exemplary alkyl groups include, but are not limited to, methyl,
ethyl, propyl,
isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3 methyl-1-
butyl, 2-methyl-
3-butyl, 2,2-dimethy1-1-propyl, 2-methyl-1-pentyl, 3 methyl-1-pentyl, 4-methyl-
1-pentyl, 2-
methy1-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethy1-1-butyl,
3,3-dimethy1-1-
butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, and
octyl.
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[0042] The term "amide" as used herein refers to the form NRaC(0)(Rb) or
C(0)NRbR,,
wherein Ra, Rb and R, are each independently selected from alkyl, alkenyl,
alkynyl, aryl,
arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The
amide can be
attached to another group through the carbon, the nitrogen, Rb, or R. The
amide also may be
cyclic, for example Rb and R,, may be joined to form a 3- to 8-membered ring,
such as 5- or 6-
membered ring. The term "amide" encompasses groups such as sulfonamide, urea,
ureido,
carbamate, carbamic acid, and cyclic versions thereof. The term "amide" also
encompasses an
amide group attached to a carboxy group, e.g., amide-COOH or salts such as
amide-COONa, an
amino group attached to a carboxy group (e.g., amino-COOH or salts such as
amino-COONa).
[0043] The term "amine" or "amino" as used herein refers to the form NRdRe or
N(Rd)Re
, where Rd and Re are independently selected from alkyl, alkenyl, alkynyl,
aryl, arylalkyl,
carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen. The
amino can be
attached to the parent molecular group through the nitrogen. The amino also
may be cyclic, for
example any two of Rd and Re may be joined together or with the N to form a 3-
to 12-
membered ring (e.g., morpholino or piperidinyl). The term amino also includes
the
corresponding quaternary ammonium salt of any amino group. Exemplary amino
groups
include alkylamino groups, wherein at least one of Rd and Re is an alkyl
group. In some
embodiments Rd and Re each may be optionally substituted with hydroxyl,
halogen, alkoxy,
ester, or amino.
[0044] The term "aryl" as used herein refers to a mono-, bi-, or other multi
carbocyclic,
aromatic ring system. The aryl group can optionally be fused to one or more
rings selected from
aryls, cycloalkyls, and heterocyclyls. The aryl groups of this present
disclosure can be
substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl,
alkynyl, amide, amino, aryl,
arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,
halogen, haloalkyl,
heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide,
sulfinyl, sulfonyl, sulfonic
acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not
limited to,
phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as
well as benzo-fused
carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups
also include but
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are not limited to a monocyclic aromatic ring system, wherein the ring
comprises 6 carbon
atoms, referred to herein as "(C6) aryl."
[0045] The term "arylalkyl" as used herein refers to an alkyl group having at
least one
aryl substituent (e.g., aryl-alkyl). Exemplary arylalkyl groups include, but
are not limited to,
arylalkyls having a monocyclic aromatic ring system, wherein the ring
comprises 6 carbon
atoms, referred to herein as "(C6) arylalkyl."
[0046] The term "carbamate" as used herein refers to the form Rg0C(0)N(Rh),
Rg0C(0)N(Rh)R, , or OC(0)NRhR,, wherein Rg, Rh and R, are each independently
selected from
alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,
heterocyclyl, and
hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates
or heteroaryl
carbamates (e.g., wherein at least one of Rg, Rh and R, are independently
selected from aryl or
heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).
[0047] The term "carbocycle" as used herein refers to an aryl or cycloalkyl
group.
[0048] The term "carboxy" as used herein refers to COOH or its corresponding
carboxylate salts (e.g., COONa). The term carboxy also includes
"carboxycarbonyl," e.g. a
carboxy group attached to a carbonyl group, e.g., C(0)-COOH or salts, such as
C(0)-COONa.
[0049] The term "cycloalkoxy" as used herein refers to a cycloalkyl group
attached to an
oxygen.
[0050] The term "cycloalkyl" as used herein refers to a saturated or
unsaturated cyclic,
bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8
carbons, referred to
herein as "(C3-C8)cycloalkyl," derived from a cycloalkane. Exemplary
cycloalkyl groups include,
but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and
cyclopentenes.
Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl,
alkynyl, amide, amino,
aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,
halogen, haloalkyl,
heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide,
sulfinyl, sulfonyl, sulfonic
acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other
cycloalkyl saturated
or unsaturated, aryl, or heterocyclyl groups.
[0051] The term "dicarboxylic acid" as used herein refers to a group
containing at least
two carboxylic acid groups such as saturated and unsaturated hydrocarbon
dicarboxylic acids
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and salts thereof. Exemplary dicarboxylic acids include alkyl dicarboxylic
acids. Dicarboxylic
acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,
amino, aryl,
arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,
halogen, haloalkyl,
heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate,
sulfide, sulfinyl, sulfonyl,
sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include, but are
not limited to
succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic
acid, maleic acid,
phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-
)-malic acid, (+)/(-)
tartaric acid, isophthalic acid, and terephthalic acid. Dicarboxylic acids
further include carboxylic
acid derivatives thereof, such as anhydrides, imides, hydrazides (for example,
succinic
anhydride and succinimide).
[0052] The term "ester" refers to the structure C(0)0-, C(0)0Rj , RkC(0)0-R,
or
RkC(0)0-, where 0 is not bound to hydrogen, and Rj and Rk can independently be
selected from
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,
cycloalkyl, ether, haloalkyl,
heteroaryl, and heterocyclyl. Rk can be a hydrogen, but Rj cannot be hydrogen.
The ester may
be cyclic, for example the carbon atom and Rj, the oxygen atom and Rk, or Rj
and Rk may be
joined to form a 3-to 12-membered ring. Exemplary esters include, but are not
limited to, alkyl
esters wherein at least one of Rj and Rk is alkyl, such as 0-C(0) alkyl, C(0)-
0-alkyl, and alkyl
C(0)-0-alkyl. Exemplary esters also include aryl or heteoaryl esters, e.g.
wherein at least one of
Rj and Rk is a heteroaryl group such as pyridine, pyridazine, pyrimidine and
pyrazine, such as a
nicotinate ester. Exemplary esters also include reverse esters having the
structure RkC(0)0-,
where the oxygen is bound to the parent molecule. Exemplary reverse esters
include succinate,
D-argininate, L-argininate, L-lysinate and D-lysinate. Esters also include
carboxylic acid
anhydrides and acid halides.
[0053] The terms "halo" or "halogen" as used herein refer to F, Cl, Br, or I.
[0054] The term "haloalkyl" as used herein refers to an alkyl group
substituted with one
or more halogen atoms. "haloalkyls" also encompass alkenyl or alkynyl groups
substituted with
one or more halogen atoms.
[0055] The term "heteroaryl" as used herein refers to a mono-, bi-, or multi-
cyclic,
aromatic ring system containing one or more heteroatoms, for example 1 to 3
heteroatoms,
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such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one
or more
substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,
aryl, arylalkyl,
carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,
haloalkyl, heteroaryl,
heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,
sulfonic acid,
sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic
rings. Illustrative
examples of heteroaryl groups include, but are not limited to, pyridinyl,
pyridazinyl, pyrimidyl,
pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-
triazolyl, pyrazinyl,
pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl,
isoxazolyl, and oxazolyl.
Exemplary heteroaryl groups include, but are not limited to, a monocyclic
aromatic ring,
wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to
herein as
C5) heteroaryl."
[0056] The terms "heterocycle," "heterocyclyl," or "heterocyclic" as used
herein refer to
a saturated or unsaturated 3, 4, 5-, 6- or 7-membered ring containing one,
two, or three
heteroatoms independently selected from nitrogen, oxygen, and sulfur.
Heterocycles can be
aromatic (heteroaryls) or non-aromatic. Heterocycles can be substituted with
one or more
substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,
aryl, arylalkyl,
carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,
haloalkyl, heteroaryl,
heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,
sulfonic acid,
sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic, and
tetracyclic groups
in which any of the above heterocyclic rings is fused to one or two rings
independently selected
from aryls, cycloalkyls, and heterocycles. Exemplary heterocycles include
acridinyl,
benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl,
biotinyl, cinnolinyl,
dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl,
furyl, homopiperidinyl,
imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl,
isothiazolidinyl, isothiazolyl,
isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl,
piperazinyl,
piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl,
pyridazinyl, pyridyl,
pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl,
quinolinyl,
quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,
tetrahydroquinolyl,
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13
tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl,
thiopyranyl, and
triazolyl.
[0057] The terms "hydroxy" and "hydroxyl" as used herein refer to -OH.
[0058] The term "hydroxyalkyl" as used herein refers to a hydroxy attached to
an alkyl
group.
[0059] The term "hydroxyaryl" as used herein refers to a hydroxy attached to
an aryl
group.
[0060] The term "ketone" as used herein refers to the structure C(0)-R, (such
as acetyl,
C(0)CH3) or R,-C(0)-R0. The ketone can be attached to another group through R,
or Ro. R, and
Ro can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R, and
Ro can be joined to
form a 3- to 12 membered ring.
[0061] The term "phenyl" as used herein refers to a 6-membered carbocyclic
aromatic
ring. The phenyl group can also be fused to a cyclohexane or cyclopentane
ring. Phenyl can be
substituted with one or more substituents including alkoxy, aryloxy, alkyl,
alkenyl, alkynyl,
amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,
ether, formyl,
halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate,
sulfide, sulfinyl,
sulfonyl, sulfonic acid, sulfonamide and thioketone.
[0062] The term "thioalkyl" as used herein refers to an alkyl group attached
to a sulfur
(S-alkyl).
[0063] "Alkyl," "alkenyl," "alkynyl", "alkoxy", "amino" and "amide" groups can
be
optionally substituted with or interrupted by or branched with at least one
group selected from
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,
carbamate, carbonyl,
carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,
heteroaryl, heterocyclyl,
hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,
sulfonamide, thioketone,
ureido and N. The substituents may be branched to form a substituted or
unsubstituted
heterocycle or cycloalkyl.
[0064] As used herein, a suitable substitution on an optionally substituted
substituent
refers to a group that does not nullify the synthetic or pharmaceutical
utility of the compounds
of the present disclosure or the intermediates useful for preparing them.
Examples of suitable
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substitutions include, but are not limited to: CI-Cs alkyl, C2-C8 alkenyl or
alkynyl; C6 aryl, 5- or 6-
membered heteroaryl; C3.C7cycloalkyl; CI-Cs alkoxy; C6 aryloxy; CN; OH; oxo;
halo, carboxy;
amino, such as NH(C1-C8 alkyl), N(C1-C8 alky1)2, NH((C6)ary1), or
N((C6)ary1)2; formyl; ketones,
such as CO(C1-C8 alkyl), -00((C6 aryl) esters, such as CO2(C1-C8 alkyl) and
CO2(C6 aryl). One of
skill in art can readily choose a suitable substitution based on the stability
and pharmacological
and synthetic activity of the compound of the present disclosure.
[0065] The term "pharmaceutically acceptable composition" as used herein
refers to a
composition comprising at least one compound as disclosed herein formulated
together with
one or more pharmaceutically acceptable carriers.
[0066] The term "pharmaceutically acceptable carrier" as used herein refers to
any and
all solvents, dispersion media, coatings, isotonic and absorption delaying
agents, and the like,
that are compatible with pharmaceutical administration. The use of such media
and agents for
pharmaceutically active substances is well known in the art. The compositions
may also contain
other active compounds providing supplemental, additional, or enhanced
therapeutic
functions. The term "pharmaceutically acceptable composition" as used herein
refers to a
composition comprising at least one compound as disclosed herein formulated
together with
one or more pharmaceutically acceptable carriers.
[0067] The term "pharmaceutically acceptable prodrugs" as used herein
represents
those prodrugs of the compounds of the present invention that are, within the
scope of sound
medical judgment, suitable for use in contact with the tissues of humans and
lower animals
without undue toxicity, irritation, allergic response, commensurate with a
reasonable benefit /
risk ratio, and effective for their intended use, as well as the zwitterionic
forms, where possible,
of the compounds of Formula I. A discussion is provided in Higuchi et al.,
"Prodrugs as Novel
Delivery Systems," ACS Symposium Series, Vol. 14, and in Roche, E.B., ed.
Bioreversible Carriers
in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987,
both of which
are incorporated herein by reference.
[0068] The term "pharmaceutically acceptable salt(s)" refers to salts of
acidic or basic
groups that may be present in compounds used in the present compositions.
Compounds
included in the present compositions that are basic in nature are capable of
forming a wide
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variety of salts with various inorganic and organic acids. The acids that may
be used to prepare
pharmaceutically acceptable acid addition salts of such basic compounds are
those that form
non-toxic acid addition salts, i.e., salts containing pharmacologically
acceptable anions,
including but not limited to sulfate, citrate, matate, acetate, oxalate,
chloride, bromide, iodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,
acetate, lactate, salicylate,
citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate,
glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and
pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the
present
compositions that include an amino moiety may form pharmaceutically acceptable
salts with
various amino acids, in addition to the acids mentioned above. Compounds
included in the
present compositions, that are acidic in nature are capable of forming base
salts with various
pharmacologically acceptable cations. Examples of such salts include alkali
metal or alkaline
earth metal salts and, particularly, calcium, magnesium, sodium, lithium,
zinc, potassium, and
iron salts.
[0069] In addition, if the compounds described herein are obtained as an acid
addition
salt, the free base can be obtained by basifying a solution of the acid salt.
Conversely, if the
product is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt,
may be produced by dissolving the free base in a suitable organic solvent and
treating the
solution with an acid, in accordance with conventional procedures for
preparing acid addition
salts from base compounds. Those skilled in the art will recognize various
synthetic
methodologies that may be used to prepare non-toxic pharmaceutically
acceptable addition
salts.
[0070] The compounds of Formula I or la may contain one or more chiral centers
and/or
double bonds and, therefore, exist as stereoisomers, such as geometric
isomers, enantiomers
or diastereomers. The term "stereoisomers" when used herein consist of all
geometric
isomers, enantiomers or diastereomers. These compounds may be designated by
the symbols
"R" or "S," depending on the configuration of substituents around the
stereogenic carbon
atom. The present invention encompasses various stereoisomers of these
compounds and
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mixtures thereof. Stereoisomers include enantiomers and diastereomers.
Mixtures of
enantiomers or diastereomers may be designated "( )" in nomenclature, but the
skilled artisan
will recognize that a structure may denote a chiral center implicitly.
[0071] Individual stereoisomers of compounds for use in the methods of the
present
invention can be prepared synthetically from commercially available starting
materials that
contain asymmetric or stereogenic centers, or by preparation of racemic
mixtures followed by
resolution methods well known to those of ordinary skill in the art. These
methods of
resolution are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary,
separation of the resulting mixture of diastereomers by recrystallization or
chromatography
and liberation of the optically pure product from the auxiliary, (2) salt
formation employing an
optically active resolving agent, or (3) direct separation of the mixture of
optical enantiomers
on chiral chromatographic columns. Stereoisomeric mixtures can also be
resolved into their
component stereoisomers by well-known methods, such as chiral-phase gas
chromatography,
chiral-phase high performance liquid chromatography, crystallizing the
compound as a chiral
salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers
can also be
obtained from stereomerically-pure intermediates, reagents, and catalysts by
well-known
asymmetric synthetic methods.
[0072] Geometric isomers can also exist in the compounds of Formula I or la.
The
present invention encompasses the various geometric isomers and mixtures
thereof resulting
from the arrangement of substituents around a carbon-carbon double bond or
arrangement of
substituents around a carbocyclic ring. Substituents around a carbon-carbon
double bond are
designated as being in the "Z" or "E" configuration wherein the terms "Z" and
"E" are used in
accordance with IUPAC standards. Unless otherwise specified, structures
depicting double
bonds encompass both the E and Z isomers.
[0073] Substituents around a carbon-carbon double bond alternatively can be
referred
to as "cis" or "trans," where "cis" represents substituents on the same side
of the double bond
and "trans" represents substituents on opposite sides of the double bond. The
arrangements
of substituents around a carbocyclic ring are designated as "cis" or "trans."
The term "cis"
represents substituents on the same side of the plane of the ring and the term
"trans"
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represents substituents on opposite sides of the plane of the ring. Mixtures
of compounds
wherein the substituents are disposed on both the same and opposite sides of
plane of the ring
are designated "cis/trans."
[0074] The compounds of Formula I disclosed herein may exist as tautomers and
both
tautomeric forms are intended to be encompassed by the scope of the invention,
even though
only one tautomeric structure is depicted.
[0075] As used herein, the term "SGLT2 inhibitor" refers a substance, such as
a small
molecule organic chemistry compounds 1 kDa) or a large biomolecule such as
a peptide (e.g.,
a soluble peptide), protein (e.g., an antibody), nucleic acid (e.g., siRNA) or
a conjugate
combining any two or more of the foregoing, that possesses the activity of
inhibiting sodium-
glucose transport protein 2 (SGLT2). Non-limiting examples of SGLT2 inhibitors
include
empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin,
HM41322, bexagliflozin,
ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or a
pharmaceutically acceptable salt of
any of the foregoing. Additional examples of SGLT2 inhibitors are disclosed in
W001/027128,
W004/013118, W004/080990, EP1852439A1 , W001/27128, W003/099836,
W02005/092877,
W02006/034489, W02006/064033, W02006/117359, W02006/117360, W02007/025943,
W02007/028814, W02007/031 548, W02007/093610, W02007/128749, W02008/049923,
W02008/055870, and W02008/055940, each of which is incorporated herein by
reference in
its entirety.
[0076] As used herein, "treatment" or "treating" refers to an amelioration of
a disease
or disorder, or at least one discernible symptom thereof. In another
embodiment, "treatment"
or "treating" refers to an amelioration of at least one measurable physical
parameter, not
necessarily discernible by the patient. In yet another embodiment, "treatment"
or "treating"
refers to reducing the progression of a disease or disorder, either
physically, e.g., stabilization
of a discernible symptom, physiologically, e.g., stabilization of a physical
parameter, or both. In
yet another embodiment, "treatment" or "treating" refers to delaying the onset
or progression
of a disease or disorder. For example, treating a cholesterol disorder may
comprise decreasing
blood cholesterol levels.
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[0077] As used herein, "prevention" or "preventing" refers to a reduction of
the risk of
acquiring a given disease or disorder or a symptom of a given disease or
disorder.
[0078] The term "narrowly defined MACE" is defined as a single composite
endpoint of
Cardiovascular (CV) death, non-fatal Myocardial infarction, or stroke.
[0079] The term "broadly defined MACE" is defined as a single composite
endpoint of
Cardiovascular (CV) death, non-fatal Myocardial infarction, hospitalization
for CVD events, or
stroke.
[0080] As used herein, "cardiovascular disease events" or "CVD events" are
physical
manifestations of cardiovascular-related disorders, and include events such as
stroke, non-fatal
myocardial infarction, cardiovascular death, and hospitalization for CVD
events and congestive
heart failure. As used herein, "hospitalization for CVD events" is defined as
hospitalization for
unstable angina, symptoms of progressive obstructive coronary disease,
emergency
revascularization procedures at any time, or urgent revascularization
procedures 30 days after
the index events prior to randomization. In some embodiments, "hospitalization
for CVD
events" includes hospitalization for physical manifestations of cardiovascular-
related disorders,
including congestive heart failure. In one embodiment, the hospitalization for
CVD events is
hospitalization for congestive heart failure.
[0081] As used herein, "cardiovascular-related disorders" include:
cardiovascular death,
non-fatal myocardial infarction, stroke, hospitalization for CVD events which
includes unstable
angina, symptoms of progressive obstructive coronary disease, emergency
revascularization
procedures at any time, or urgent revascularization procedures 30 days after
index event, and
congestive heart failure.
Exemplary Embodiments of the Invention
[0082] In one embodiment, the present invention provides methods of treating
and/or
preventing Major adverse cardiovascular events (MACE), including non-fatal
myocardial
infarction, CV death, stroke, and hospitalization for CVD events, by
administering to a subject in
need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2)
inhibitor and a
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compound of Formula 1 or a stereoisomer, tautomer, pharmaceutically acceptable
salt, or
hydrate thereof, wherein:
R5
H R6
(R4)P
I
R3 w1 .
N N R7
H
R2 H
R1
0
Formula 1
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate
thereof,
wherein:
R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen,
and
hydrogen;
R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen,
and hydrogen;
R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen,
and
hydrogen;
R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and
alkoxy;
W is selected from C and N, wherein if W is N, then p is 0 or 1, and if W is
C, then p is 1;
and
for W-(R4), W is C, p is 1 and R4 is H, or W is N and p is 0.
[0083] In one embodiment, the compound of Formula 1 is 2-(4-(2-hydroxyethoxy)-
3,5-
dimethylpheny1)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a
pharmaceutically acceptable salt thereof.
[0084] In some embodiments, the SGLT2 inhibitor is selected from
empagliflozin,
canagliflozin, dapagliflozin, and HM41322. In some embodiments, the SGLT2
inhibitor is
selected from bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, and
tofogliflozin.
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[0085] In one embodiment, the MACE endpoint is narrowly defined as a single
composite endpoint of cardiovascular (CV) death, non-fatal myocardial
infarction, or stroke.
[0086] In one embodiment, the MACE endpoint is broadly defined as a single
composite
endpoint of cardiovascular (CV) death, non-fatal myocardial infarction,
hospitalization for CVD
events, or stroke.
[0087] In one embodiment, the method for treating and/or preventing any
individual
component of MACE, including cardiovascular (CV) death, non-fatal myocardial
infarction,
hospitalization for CVD events, or stroke by administrating to a subject in
need thereof, a
sodium-glucose transport protein 2 (SGLT2) inhibitor and a Compound of Formula
la or a
stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof,
wherein:
R5
H R6
(R4)P
1
I.
R3 N \/1w/ N H R7
R2 H
R1
0
Formula la
R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen;
R2 is selected from alkoxy, alkyl, and hydrogen;
R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen,
and
hydrogen;
R6 is selected from alkyl, hydroxyl, and alkoxy;
W is selected from C and N, wherein if W is N, then p is 0 or 1, and if W is
C, then p is 1; and
for W-(R4), W is C, p is 1 and R4 is H, or W is N and p is 0.
[0088] In one embodiment, the compound of Formula I is administered
simultaneously
with the SGLT2 inhibitor.
[0089] In one embodiment, the Compound of Formula I is administered
sequentially
with the SGLT2 inhibitor.
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[0090] In one embodiment, the Compound of Formula 1 is administered in a
single
pharmaceutical composition with the SGLT2 inhibitor.
[0091] In one embodiment, the Compound of Formula land the SGLT2 inhibitor are
administered as separate compositions.
[0092] In one embodiments, a subject in need thereof is given 200 mg daily of
2-(4-(2-
hydroxyethoxy)-3,5-dimethylpheny1)-5,7-dimethoxyquinazolin-4(3H)-one or an
equivalent
amount of a pharmaceutically acceptable salt thereof.
[0093] In one embodiment, a subject in need thereof is given 100 mg of 2-(4-(2-
hydroxyethoxy)-3,5-dimethylpheny1)-5,7-dimethoxyquinazolin-4(3H)-one or an
equivalent
amount of a pharmaceutically acceptable salt thereof twice daily.
[0094] In one embodiment, the subject is a human.
[0095] In one embodiment, the subject is a human with type 2 diabetes and low
HDL
cholesterol (below 40mg/dL for males and below 45 mg/dL for females) and a
recent acute
coronary syndrome (ACS) (preceding 7-90 days).
[0096] In one embodiment, the subject is a human with type 2 diabetes.
[0097] In one embodiment, the subject is a human with low HDL cholesterol
(i.e., below
40mg/dL for males and below 45 mg/dL for females).
[0098] In one embodiment, the subject is a human with a recent ACS (preceding
7-90
days).
[0099] In one embodiment, the subject is a human on statin therapy.
References
Cannon, C. P., Blazing, M. A., Giugliano, R. P., et al. (2015) Ezetimibe added
to statin therapy
after acute coronary syndromes. N Engl J Med, 372(25), 2387-97.
Schwartz, G. G., Olsson, A. G. & Barter, P. J. (2013) Dalcetrapib in patients
with an acute
coronary syndrome. N Engl J Med, 368(9), 869-70.
Schwartz, G. G., Steg, P. G., Szarek, M., et al. (2018) Alirocumab and
cardiovascular outcomes
after acute coronary syndrome. N Engl J Med, 379(22), 2097-107.
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22
Zinman, B., Wanner, C., Lachin, J. M., et al. (2015) Empagliflozin,
cardiovascular outcomes, and
mortality in type 2 diabetes. N Engl J Med, 373(22), 2117-28.
Neal B., Perkovic V., Mahaffey, K. W., et al. (2017) Canagliflozin and
cardiovascular and renal
events in type 2 diabetes. N Engl J Med, 377(7), 644-657.
Perkovic, V., Jardine, M. J., Neal, B., et al. (2019) Canagliflozin and renal
outcomes in type 2
diabetes and nephropathy. N Engl J Med, 380(24), 2295-2306.
Guettier, J.M. (2016) Endocrinologic and Metabolic Drugs Advisory Committee
(EMDAC)
Meeting. U.S. Food and Drug Administration (FDA).
Rastogi, A., Bhansali, A. (2017) SGLT2 Inhibitors Through the Windows of EMPA-
REG
and CANVAS Trials: A Review. Diabetes Ther, 8, 1245-1251.
Carbone S., Dixon, D.L. (2019) The CANVAS Program: implications of
canaglifozin on reducing
cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovasc
Diabetol, 18(64), 1-13.
Wiviott, S.D., Raz, M.P., et al. (2019) Dapagliflozin and Cardiovascular
Outcomes
in Type 2 Diabetes. N Engl J Med, 380(4), 347-357.
Examples
Example 1: Clinical Development
[0100] Apabetalone (RVX-208) was evaluated in a recently completed clinical
Phase 3
trial (BETonMACE; NCT02586155) for the effect on MACE in type 2 diabetes
patients with low
HDL cholesterol (below 40 mg/dL for males and below 45 mg/dL for females) and
a recent
acute coronary syndrome (ACS) (preceding 7-90 days). All patients received
high intensity
statin treatment as well as other evidence-based treatments.
[0101] Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2
diabetes
and low HDL cholesterol (40mg/dIfor men, 45 mg/di for women), receiving
intensive or
maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in
double-blind
fashion to receive apabetalone 100 mg orally twice daily or matching placebo.
Baseline
characteristics include female sex (25%), myocardial infarction as index ACS
event(74%),
coronary revascularization for index ACS (76%), treatment with dual anti-
platelet therapy (87%)
and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg
per deciliter, and
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median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of
cardiovascular
death, non-fatal myocardial infarction, or stroke. Assumptions include a
primary event rate of
7% per annum in the placebo group and median follow-up of 1.5 years. Patients
were followed
until at least 250 primary endpoint events had occurred, providing 80% power
to detect a 30%
reduction in the primary endpoint with apabetalone.
Example 2: Post-hoc Analysis
[0102] In the BETonMACE clinical study, a total of N=298 patients (N=150 in
apabetalone treatment group and N=148 in placebo treatment group) were
administered an
SGLT2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) in addition
to RVX-208 with
specified statin therapy (atorvastatin and rosuvastatin) and other guideline-
defined treatments.
Patients who were randomized and received at least one dose of SGLT2 treatment
prior to the
date of the first incidence of event were censored as a MACE event at the date
of the
confirmed event. Those patients who received at least one dose of SGLT2
treatment after the
date of the first incidence of event were censored as non-MACE events and the
date of last
contact was used as the censoring date. For all patients who did not receive
SGLT2 treatment
during the study, the time to first event was calculated using randomization
date and date of
the confirmed event, or date of last contact for censored subjects.
[0103] The distributions of the endpoints within the apabetalone and placebo
groups
were compared using a two-sided log-rank test (LRT) with an alpha = 0.05 level
of significance.
The cumulative incidence is shown as 1-KM (Kaplan-Meier) estimate for event
rate.
Narrowly defined MACE
[0104] Figures 1-3 each compare the cumulative incidence of narrowly defined
MACE
(i.e., as a single composite endpoint of multiple primary end points defined
as cardiovascular
death, non-fatal myocardial infarction, or stroke) between two groups of
patients, a test group
and a control group, which are described as follows:
i. patients treated with a SGLT2 inhibitor and apabetalone (test) and
patients
treated with a SGLT2 inhibitor and received a placebo (control) (Figure 1);
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ii. patients not treated with a SGLT2 inhibitor but treated with
apabetalone (test)
and patients not treated with SGLT2 inhibitor but received placebo (control)
(Figure 2); and
iii. patients treated with apabetalone and a SGLT2 inhibitor (test) and
patients
treated apabetalone only (control) (Figure 3).
[0105] In Figure 1, where the patients were treated with SGLT2 inhibitors and
received
either apabetalone or a placebo, there were a total of 18 primary end points:
5 (3.3%) in the
apabetalone group and 13 (8.9%) in the placebo group, representing a Kaplan-
Meier estimated
event rate of 2.7% in the apabetalone group and 5.4% in the placebo group at
18 months. This
means that at 18 months, patients treated with only the SGLT2 inhibitor had an
estimated
narrowly defined MACE event rate at 5.4% but when patients were treated with
the
combination of apabetalone and a SGLT2 inhibitor, the estimated narrowly
defined MACE event
rate was halved at 2.7%. As depicted in Figure 1, combining apabetalone with
an SGLT2
inhibitor significantly reduced the composite end point of narrowly defined
MACE compared to
treatment with the SGLT2 inhibitor alone, specifically by reducing the number
of patients
having a narrowly defined MACE event at any given time by 60% (Hazard Ratio
[HR], 0.40;
95%Cl, 0.16-1.00; P = 0.05).
[0106] In Figure 2, where the patients were not treated with a SGLT2 inhibitor
but
received either apabetalone or a placebo, there were a total of 214 primary
end points: 111
(10.5%) in the apabetalone group and 130 (12.3%) in the placebo group,
representing a Kaplan-
Meier estimated event rate of 8.0% in the apabetalone group and 9.8% in the
placebo group at
18 months. This means that at 18 months, patients treated with only
apabetalone had an
estimated narrowly defined MACE event rate of 10.5% while patients that were
not treated
with apabetalone or an SGLT2 inhibitor had an estimated narrowly defined MACE
event rate of
12.3%. As depicted in Figure 2, apabetalone monotherapy slightly reduced the
composite end
point of narrowly defined MACE compared to non-treatment, specifically by
reducing the
number of patients having a narrowly defined MACE event at any given time by
16% (Hazard
Ratio [HR], 0.84; 95%Cl, 0.65-1.08; P = 0.18).
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[0107] As depicted in Figure 3, patients treated with the combination of
apabetalone
and a SGLT2 inhibitor, when compared to patients treated with apabetalone
alone, exhibited a
significant hazard ratio of 0.47 (95%Cl, 0.27-0.81; P = 0.007) for the
composite end point of
narrowly defined MACE. This means that the combination of apabetalone and a
SGLT2
inhibitor reduced the number of patients having a narrowly defined MACE event
at any given
time by 53%, compared to treatment with apabetalone alone.
[0108] In conclusion, apabetalone monotherapy was able to reduce the number of
patients having a narrowly defined MACE event at any given time by 16%
compared to non-
treatment (see Figure 2). Thus, it was unexpected that a combination therapy
of apabetalone
and SGLT2 results in a significant reduction of the number of patients having
a narrowly defined
MACE event at any given time by 60% compared to SGLT2 monotherapy.
Broadly defined MACE
[0109] Figures 4-6 each compare the cumulative incidence of broadly defined
MACE
(i.e., as a single composite endpoint of multiple primary end points defined
as cardiovascular
death, non-fatal myocardial infarction, stroke, or hospitalization for
cardiovascular diseases
(CVD)) between the same two groups of patients as described above for Figures
1-3.
[0110] In Figure 4, where the patients were treated with SGLT2 inhibitors and
received
either apabetalone or a placebo, it can be seen that combining apabetalone
with an SGLT2
inhibitor reduced the composite end point of broadly defined MACE compared to
treatment
with the SGLT2 inhibitor alone (with trending statistical significance),
specifically by reducing
the number of patients having a broadly defined MACE event at any given time
by 50% (Hazard
Ratio [HR], 0.50; 95%Cl, 0.22-1.11; P = 0.09).
[0111] In Figure 5, where the patients were not treated with a SGLT2 inhibitor
but
received either apabetalone or a placebo, it can be seen that apabetalone
monotherapy slightly
reduced the composite end point of broadly defined MACE compared to non-
treatment,
specifically by reducing the number of patients having a broadly defined MACE
event at any
given time by 13% (Hazard Ratio [HR], 0.87; 95%Cl, 0.69-1.10; P = 0.25).
[0112] As depicted in Figure 6, patients treated with the combination of
apabetalone
and a SGLT2 inhibitor, when compared to patients treated with apabetalone
alone, exhibited a
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significant hazard ratio of 0.54 (95%Cl, 0.33-0.89; P = 0.02) for the
composite end point of
broadly defined MACE. This means that the combination of apabetalone and a
SGLT2 inhibitor
reduced the number of patients having a broadly defined MACE event at any
given time by
46%, compared to treatment with apabetalone alone.
[0113] In conclusion, in view of the modest ability of although apabetalone
monotherapy modestly to reduce the number of patients having a broadly defined
MACE event
at any given time by 13% compared to non-treatment (see Figure 5), it was
surprising and
unexpected that the combination therapy of apabetalone and SGLT2 significantly
reduces the
number of patients having a broadly defined MACE event at any given time by
50% compared
to SGLT2 monotherapy.
Non-fatal myocardial infarction
[0114] Figures 7-9 each compare the cumulative incidence of non-fatal
myocardial
infarction between the same two groups of patients as described as described
above for Figures
1-3.
[0115] In Figure 7, where the patients were treated with SGLT2 inhibitors and
received
either apabetalone or a placebo, it can be seen that combining apabetalone
with an SGLT2
inhibitor significantly reduced for the end point of non-fatal myocardial
infarction compared to
treatment with the SGLT2 inhibitor alone, specifically by reducing the number
of patients
having a non-fatal myocardial infarction event at any given time by 69%
(Hazard Ratio [HR],
0.31; 95%Cl, 0.11-0.88; P = 0.03).
[0116] In Figure 8, where the patients were not treated with a SGLT2 inhibitor
but
received either apabetalone or a placebo, it can be seen that apabetalone
monotherapy
reduced the end point of non-fatal myocardial infarction compared to non-
treatment,
specifically by reducing the number of patients having a non-fatal myocardial
infarction event
at any given time by 15% (Hazard Ratio [HR], 0.85; 95%Cl, 0.61-1.17; P =
0.31).
[0117] As depicted in Figure 9, patients treated with the combination of
apabetalone
and a SGLT2 inhibitor, when compared to patients treated with apabetalone
alone, exhibited a
significant hazard ratio of 0.47 (95%Cl, 0.33-0.89; P = 0.03) for the end
point of non-fatal
myocardial infarction. This means that the combination of apabetalone and a
SGLT2 inhibitor
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reduced the number of patients having a non-fatal myocardial infarction event
at any given
time by 53%, compared to treatment with apabetalone alone.
[0118] In conclusion, given that apabetalone monotherapy reduced the number of
patients having a non-fatal myocardial infarction event at any given time by a
modest 15%
compared to non-treatment (see Figure 8) , it was therefore unexpected that
the combination
therapy of apabetalone and SGLT2 significantly reduces the number of patients
having a non-
fatal myocardial infarction event at any given time by 69% compared to SGLT2
monotherapy.
Cardiovascular death
[0119] Figures 10-12 each compare the cumulative incidence of cardiovascular
death
between the same two groups of patients as described as described above for
Figures 1-3.
[0120] In Figure 10, where the patients were treated with SGLT2 inhibitors and
received
either apabetalone or a placebo, it can be seen that combining apabetalone
with an SGLT2
inhibitor significantly reduced the end point of cardiovascular death compared
to treatment
with the SGLT2 inhibitor alone, specifically by reducing the number of
patients having a
cardiovascular death event at any given time by 60% (Hazard Ratio [HR], 0.40;
95%Cl, 0.06-2.88;
P = 0.36).
[0121] In Figure 11, where the patients were not treated with a SGLT2
inhibitor but
received either apabetalone or a placebo, it can be seen that apabetalone
monotherapy
reduced the end point of cardiovascular death compared to non-treatment,
specifically by
reducing the number of patients having a cardiovascular death event at any
given time by 16%
(Hazard Ratio [HR], 0.84; 95%Cl, 0.56-1.25; P = 0.39).
[0122] As depicted in Figure 12, patients treated with the combination of
apabetalone
and a SGLT2 inhibitor, when compared to patients treated with apabetalone
alone, exhibited a
significant hazard ratio of 0.39 (95%Cl, 0.16-0.95; P = 0.04) for the end
point of cardiovascular
death. This means that the combination of apabetalone and a SGLT2 inhibitor
reduces the
number of patients having a cardiovascular death event at any given time by
61%, compared to
treatment with apabetalone alone.
[0123] In conclusion, given that apabetalone monotherapy reduced the number of
patients having a cardiovascular death event at any given time by a modest 16%
compared to
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patients receiving only the placebo (see Figure 11) , it was unexpected that
the combination
therapy of apabetalone and SGLT2 would result in a significant reduction in
the number of
patients having a non-fatal myocardial infarction event at any given time by
60% compared to
SGLT2 monotherapy.
Hospitalization for cardiovascular diseases
[0124] Figures 13-15 each compare the cumulative incidence of hospitalization
for
cardiovascular diseases between the same two groups of patients as described
as described
above for Figures 1-3.
[0125] In Figure 13, where the patients were treated with SGLT2 inhibitors and
received
either apabetalone or a placebo, it can be seen that combining apabetalone
with a SGLT2
inhibitor significantly reduced the end point of hospitalization for
cardiovascular diseases
compared to treatment with the SGLT2 inhibitor alone, specifically by reducing
the number of
patients having a hospitalization for cardiovascular diseases event at any
given time by 52%
(Hazard Ratio [HR], 0.48; 95%Cl, 0.18-1.27; P = 0.14).
[0126] In Figure 14, where the patients were not treated with a SGLT2
inhibitor but
received either apabetalone or a placebo, it can be seen that apabetalone
monotherapy slightly
reduced the end point of hospitalization for cardiovascular diseases compared
to non-
treatment, specifically by reducing the number of patients having a
hospitalization for
cardiovascular diseases event at any given time by 13% (Hazard Ratio [HR],
0.87; 95%Cl, 0.60-
1.27; P = 0.47),
[0127] As depicted in Figure 15, patients treated with the combination of
apabetalone
and a SGLT2 inhibitor, when compared to patients treated with apabetalone
alone, exhibited a
significant hazard ratio of 0.70 (95%Cl, 0.32-1.52; P = 0.37) for the end
point of hospitalization
for cardiovascular diseases. This means that the combination of apabetalone
and a SGLT2
inhibitor reduced the number of patients having a hospitalization for
cardiovascular diseases
event at any given time by 30%, compared to treatment with apabetalone alone.
[0128] In conclusion, given that apabetalone monotherapy reduces the number of
patients having a hospitalization for cardiovascular diseases event at any
given time by 13%
compared to non-treatment (see Figure 14) , it was therefore unexpected that
the combination
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therapy of apabetalone and SGLT2 would significantly reduce the number of
patients having a
hospitalization for cardiovascular diseases event at any given time by 52%
compared to SGLT2
monotherapy.
Hospitalization for congestive heart failure
[0129] Figures 16-18 each compare the cumulative incidence of hospitalization
for
congestive heart failure between the same two groups of patients as described
as described
above for Figures 1-3.
[0130] In Figure 16, where the patients were treated with SGLT2 inhibitors and
received
either apabetalone or a placebo, it can be seen that combining apabetalone
with an SGLT2
inhibitor significantly reduced the end point of hospitalization for
congestive heart failure
compared to treatment with the SGLT2 inhibitor alone, specifically by reducing
the number of
patients having a hospitalization for congestive heart failure event at any
given time by 51%
(Hazard Ratio [HR], 0.49; 95%Cl, 0.05-4.73; P = 0.54).
[0131] In Figure 17, where the patients were not treated with a SGLT2
inhibitor but
received either apabetalone or a placebo, it can be seen that apabetalone
monotherapy
reduced the end point of hospitalization for congestive heart failure compared
to non-
treatment, specifically by reducing the number of patients having a
hospitalization for
congestive heart failure event at any given time by 39% (Hazard Ratio [HR],
0.61; 95%Cl, 0.38-
0.97; P = 0.04),
[0132] As depicted in Figure 18, patients treated with the combination of
apabetalone
and a SGLT2 inhibitor, when compared to patients treated with apabetalone
alone, exhibited a
hazard ratio of 0.44 (95%Cl, 0.14-1.33; P = 0.14) for the end point of
hospitalization for
congestive heart failure. This means that the combination of apabetalone and a
SGLT2 inhibitor
reduced the number of patients having a hospitalization for congestive heart
failure event at
any given time by 56%, compared to treatment with apabetalone alone.
[0133] In conclusion, given that apabetalone monotherapy was able to only
reduce the
number of patients having a hospitalization for congestive heart failure event
at any given time
by 39% compared to patients receiving only the placebo (see Figure 17) , it
was therefore
unexpected that the combination therapy of apabetalone and SGLT2 would be
capable of
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significantly reducing the number of patients having a hospitalization for
congestive heart
failure event at any given time by 51% compared to SGLT2 monotherapy.
